Persisting challenges in the development of predictive biomarkers for immuno-oncology therapies for renal cell carcinoma

Introduction: Immuno-oncology (IO) therapies have become integral to renal cell carcinoma (RCC) management, RCC remains a complex malignancy with diverse clinical behaviors and a heterogeneous tumor microenvironment, highlighting the need for predictive biomarkers to optimize therapy. Areas covered: This review synthesizes recent findings from clinical trials, translational studies, and molecular analyses to provide an updated perspective on biomarker research for IO therapies in RCC. A literature search was conducted using PubMed, Embase, and Web of Science for articles published between January 2010 and November 2024. Expert opinion: IO combination therapies have demonstrated significant improvements in progressionfree survival and overall survival compared with sunitinib. However, treatment outcomes vary according to the IMDC risk groups, metastatic sites, and histological subtypes, such as sarcomatoid differentiation. Advances in molecular biology have elucidated the roles of genetic alterations and immune phenotypes in modulating IO efficacy. Emerging biomarkers, including tertiary lymphoid structures, human endogenous retroviruses, and the gut microbiome, show promise but require further validation. Addressing challenges such as intratumoral heterogeneity and dynamic immune responses will be key to identifying actionable biomarkers. Continued integration of clinical and molecular insights is essential for improving patient selection and outcomes in RCC treated with IO therapies.